This application is a 371 of PCT/JP99/05584, filed on Oct. 8, 1999.
The present invention relates to an oxidative stress inhibitor useful for prevention, retardation, alleviation or treatment of diseases or dermal injuries or diseases caused by an oxidative stress; a method for inhibiting an oxidative stress by using such an oxidative stress inhibitor; and a cosmetic composition or dermatologic preparation for external use which comprises such an oxidative stress inhibitor as an effective ingredient.
In recent years, causes of diseases or dermal injuries or diseases brought about by an oxidative stress such as ultraviolet rays, active oxygen, free radicals or the like have been searched briskly. For example, it is known that cytotoxic cytokines such as IL-1xcex1, TNF-xcex1 and the like or extracellular matrix proteases such as collagenase and the like are closely related to aging, canceration or malignant alteration, edema, pigmentation or the like as its cause (for example, xe2x80x9cOxidative Stress in Dermatologyxe2x80x9d, Marcel Dekker, Inc., pp. 187-205, 1993). Expression of a gene coding for such a protein is mainly controlled at the level of genetic transcription, whereas, regarding cytotoxic proteins such as cytotoxic cytokines and extracellular matrix proteases, it is controlled by a transcriptional regulatory factor such as NF-xcexaB or AP-1 (for example, xe2x80x9cActive oxygen and Signal transmissionxe2x80x9d, Kodansha Scientific, pp. 37-46, 1996). In practice, NF-xcexaB and AP-1 are known to be activated by an oxidative stress and promote the expression of cytotoxic protein (for example, xe2x80x9cActive oxygen and Signal transmissionxe2x80x9d, Kodansha Scientific, pp. 1-20, 1996). Diseases or dermal injuries or diseases caused by an oxidative stress are therefore expected to be prevented, retarded, alleviated or treated if it becomes possible to suppress the activation of NF-xcexaB or AP-1 due to an oxidative stress.
There is a description that the activation of NF-xcexaB is inhibited by a sulfur-containing antioxidant such as N-acetyl-L-cysteine or pyrrolidine dithiocarbamate (for example, xe2x80x9cActive oxygen and Signal transmissionxe2x80x9d, Kodansha Scientific, pp. 37-46, 1996). It is reported that N-acetyl-L-cysteine can also suppress the activation of AP-1 (for example, xe2x80x9cFEBS Lettersxe2x80x9d, Vol. 384, pp. 92-96, 1996). These compounds are, however, accompanied with such drawbacks as insufficient effects or strong cytotoxicity. Sulfur-containing compounds such as N,Nxe2x80x2-diacetyl-L-cystine are known to suppress dermal inflahmmation induced by leukotrienes (ex. U.S. Pat. No. 4,827,016), but not known to inhibit cytokines or transcription factor taking part in aging, canceration, edema, pigmentation or the like. In addition to sulfur-containing antioxidants, there are reports on retinoic acid used for inhibiting the activation of AP-1 and the expression of extracellular matrix proteases (for example, xe2x80x9cNaturexe2x80x9d, Vol. 379, pp. 335-339, 1996); and steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs used for suppressing the activation of NF-xcexaB (for example, xe2x80x9cBio Essaysxe2x80x9d, Vol. 18, pp. 373-378, 1996). Retinoic acid and steroidal anti-inflammatory drugs are not free from side effects such as detachment of the skin and steroid-induced skin diseases, respectively, so that they cannot be used freely. Non-steroidal anti-inflammatory drugs do not cause systemic side effects which are observed upon use of a steroidal anti-inflammatory drug, but there is room for improvement in its local side effects. In addition, its effects for suppressing the activation of inflammatory factors are insufficient.
As one of the diseases or dermal injuries or diseases caused by an oxidative stress, a change in the skin due to aging or an undesirable esthetic change in the skin can be mentioned. It is reported that in order to prevent or retard such a change, a natural extract having action for alleviating skin roughness or the component contained therein, such as astaxantin, and a cystine derivative are in combination applied to the skin (for example, Japanese Patent Application Laid-Open: (Kokai) No. Hei 9-143,063). According to the report, such a combination contributes to the recovery of resilience or luster of the skin or the amelioration of the somber coloring,-but does not exhibit sufficient effects. In addition, its effects against skin wrinkles or flabby skin, the most eminent symptoms in the observation of the aged skin, are, however, not revealed.
Induction or promotion of skin wrinkles or flabby skin is a typical example of skin change due to aging or an undesirable aesthetic skin change, both brought about by an oxidative stress. The sun light or ultraviolet rays therefrom can be mentioned as its cause (for example, xe2x80x9cShin Keshohin-gakuxe2x80x9d, Nanzando, pp. 38-46, 1993). As a method for preventing or retarding such a change, application of an antioxidant such as tocopherol, ascorbic acid, N-acetyl-L-cysteine or the like to the kin is reported (for example, xe2x80x9cPhotodermatol. Photoimmunol. Photomed., Vol.7, pp. 56-62, 1990 or Japanese Language Laid-Open Publication (PCT) No. Hei 6-510,542). Prevention or retardation is also effected by the application of an anti-inflammatory drug or an ultraviolet absorber, other than an antioxidant (for example, xe2x80x9cPhotodermatol. Photoimmunol. Photomed., Vol.7, pp. 153-158, 1990 or J. Photochem. Photobiol. B: Biol., Vol. 9, pp. 323-334, 1991) or improvement is conducted using retinoic acid (for example, xe2x80x9cJ. Invest. Dermatol., Vol. 98, pp. 248-254, 1992). These compounds are, however, accompanied with the problems such as insufficient effects, strong cytotoxicity and low light stability. Moreover, anti-inflammatory drugs and retinoic acid are not free from side effects as described above.
Objects of the present invention are to provide, based on the above-described background art, an oxidative stress inhibitor which is capable of suppressing the activation of a gene transcriptional regulatory factor taking part in the expression of a cytotoxic protein and exhibits good feeling upon use and safety; to provide a method for preventing, retarding, alleviating or treating a skin change due to aging or an undesirable aesthetic skin change, both caused or promoted by an oxidative stress; and to provide a cosmetic composition or dermatologic preparation for external use comprising the oxidative stress inhibitor as an effective ingredient.
The present inventors have proceeded with an extensive investigation with a view toward attaining the above-described objects. As a result, they have found that the above-described objects can be attained by using a cysteine or cystine derivative represented by the below-described general formula (I), (II) or (III) or a salt thereof as an effective ingredient; or by using a cysteine or cystine derivative represented by the below-described general formula (IV) or a salt thereof and an antioxidant, anti-inflammatory drug or ultraviolet absorber in combination. Based on these findings, the present invention has been completed.
Accordingly, the present invention relates to an oxidative stress inhibitor which comprises as an effective ingredient at least one selected from the cysteine or cystine derivatives represented by the below-described general formula (I) and the salts thereof. 
In the above-described general formula (I), R1 represents a hydrogen atom, an aminocarbonyl group, an acyl group having 2-22 carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms; the two E""s represent, each independently, a hydrogen atom or an alkyl group having 1-6 carbon atoms, and g stands for an integer of 0 to 5, while R2 represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms, with the proviso that when R1 represents a hydrogen atom or an acyl group having 2-3 carbon atoms, R2 represents an alkyl group having 6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms. R3 represents a hydrogen atom, an aminocarbonyl group, an acyl group having 2-22 carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms, a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atom or a group represented by the following general formula (1). 
In the above-described general formula (1), R4 represents a hydrogen atom, an aminocarbonyl group, an acyl group having 2-22 carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms; the two F""s represent, each independently, a hydrogen atom or an alkyl group having 1-6 carbon atoms, and h stands for an integer of 0 to 5, while R5 represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms, with the proviso that when R4 represents a hydrogen atom or an acyl group having 2-3 carbon atoms, R5 represents an alkyl group having 6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms.
The cysteine or cystine derivatives represented by the above-described general formula (I) are not known in the literature, and therefore, are new compounds. Accordingly, the present invention relates also to the cysteine or cystine derivatives represented by the above-described general formula (I) and the salts thereof per se.
The present invention relates also to an oxidative stress inhibitor which comprises as an effective ingredient at least one selected from the cystine derivatives represented by the below-described general formula (II) and the salts thereof. 
In the above-described general formula (II), R6 and R8 represent a hydrogen atom, an aminocarbonyl group, an acyl. group having 2-22 carbon-atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms; the two T""s and the two V""s represent, each independently, a hydrogen atom or an alkyl group having 1-6 carbon atoms, and i and j stand, each independently, for an integer of 0 to 5, while R7 and R9 represent a hydrogen atom, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms, with the proviso that when R6 and R8 represent a hydrogen atom or an acyl group having 2 carbon atoms, and i and j are each 1, R7 and R9 represent an alkyl group having 2-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms.
Also, the present invention relates to a preventing and/or treating agent for oxidative stress-induced diseases, inter alia, ultraviolet rays-induced diseases, which agent comprises at least one selected from the cysteine or cystine derivatives represented by the above-described general formula (I) or (II) and the salts thereof.
Furthermore, the present invention relates to a cosmetic additive to be added as a component to a cosmetic composition, which additive consists of at least one selected from the cysteine or cystine derivatives represented by the above-described general formula (I) or (II) and the salts thereof.
Still furthermore, the present invention relates to a cosmetic composition or a dermatologic preparation for external use which comprises at least one selected from the cysteine or cystine derivatives represented by the above-described general formula (I) or (II) and the salts thereof. The cosmetic composition of the present invention is useful for preventing or alleviationg oxidative stress-induced dermal injuries, and the dermatologic preparation for external use of the present invention is useful for preventing or treating oxidative stress-induced diseases.
Furthermore, the present invention relates to a method for preventing, retarding, alleviating or treating a skin change due to aging or an undesirable aesthetic skin change, both caused or promoted by an oxidative stress, which method comprises applying onto the skin a cosmetic composition or a dermatologic preparation for external use comprising, as an effective ingredient, at least one selected from the cysteine or cystine derivatives represented by the above-described general formula (I) or the below-described general formula (III) and the salts thereof. 
In the above-described general formula (III), R10 and R12 represent a hydrogen atom, an aminocarbonyl group, an acyl group having 2-22 carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms; the two W""s and the two X""s represent, each independently, a hydrogen atom or an alkyl group having 1-6 carbon atoms, and k and 1 stand, each independently, for an integer of 0 to 5, while R11and R13 represent a hydrogen atom, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms, with the proviso that when R10 and R12 represent a hydrogen atom or an acyl group having 2 carbon atoms, and k and l are each 1, R11 and R13 represent an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms.
Moreover, the present invention relates to a cosmetic composition or a dermatologic preparation for external use which comprises Component (A) and Component (B), each described below.
Component (A): At least one selected from the cysteine or cystine derivatives represented by the below-described general formula (IV) and the salts thereof. 
In the above-described general formula (IV), R4 represents a hydrogen atom, an aminocarbonyl group, an acyl group having 2-22 carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms; the two Y""s represent, each independently, a hydrogen atom or an alkyl group having 1-6 carbon atoms, and m stands for an integer of 0 to 5, while A representsxe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94, R15 represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atom or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms, and R16 represents a hydrogen atom, an aminocarbonyl group an acyl group having 2-22 carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms, a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms, or a group represented by the below-described general formula (2), with the proviso that when R14 represents a hydrogen atom or when R14 represents an aminocarbonyl group or an acyl group having 2 carbon atoms and A represents xe2x80x94Oxe2x80x94, R15 represents an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms. 
In the above-described general formula (2), R17 represents a hydrogen atom, an aminocarbonyl group, an acyl group having 2-22 carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms; the two Z""s represent, each independently, a hydrogen atom or an alkyl group having 1-6 carbon atoms, and n stands for an integer of 0 to 5, while B represents xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94, and R18 represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms, with the proviso that when R17 represents a hydrogen atom or when R17 represents an aminocarbonyl group or an acyl group having 2 carbon atoms and B represents xe2x80x94Oxe2x80x94, R18 represents an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms.
Component (B): At least one selected from an anti-oxidant, anti-inflammatory drug and ultraviolet absorbor.
Hereinbelow will be described the present invention in greater detail.
First, specific examples of the compounds relating to the present invention will be described.
In the cysteine or cystine derivative represented by the above-described general formula (I), (II), (III) or (IV), or the salts thereof, as R1, R4, R6, R8, R10, R12, R14 and R17, there may be mentioned hydrogen atom and aminocarbonyl, acetyl, propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl, tert-butyryl, n-valeryl, sec-valeryl, pivaloyl, isovaleryl, n-hexanoyl, cyclohexanoyl, n-heptanoyl, n-octanoyl, 2-ethylhexanoyl, nonanoyl, isononanoyl, decanoyl, isodecanoyl, undecanoyl, lauroyl, tridecanoyl, isotridecanoyl, myristoyl, palmitoyl, isopalmitoyl, stearoyl, isostearoyl, oleoyl, docosanoyl, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-amyl, sec-amyl, tert-amyl, isoamyl, n-hexyl, cyclohexyl, n-heptyl, n-octyl, 2-ethylhexyl, nonyl, isononyl, decyl, isodecyl, undecyl, lauryl, tridecyl, isotridecyl, myristyl, cetyl, isocetyl, stearyl, isostearyl, oleyl, behenyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxyisopropyl, 2-hydroxy-n-butyl, 2-hydroxyisobutyl, 2-hydroxy-sec-butyl, 2-hydroxy-tert-butyl, 2-hydroxy-n-amyl, 2-hydroxy-sec-amyl, 2-hydroxy-tert-amyl, 2-hydroxyisoamyl, 2-hydroxy-n-hexyl, 2-hydroxycyclohexyl, 2-hydroxy-n-heptyl, 2-hydroxy-n-octyl, 2-hydroxy-2-ethylhexyl, 2-hydroxynonyl, 2-hydroxyisononyl, 2-hydroxydecyl, 2-hydroxyisodecyl, 2-hydroxyundecyl, 2-hydroxylauryl, 2-hydroxytridecyl, 2-hydroxyisotridecyl, 2-hydroxymyristyl, 2-hydroxycetyl, 2-hydroxyisocetyl, 2-hydroxystearyl, 2-hydroxyisostearyl, 2-hydroxyoleyl, 2-hydroxybehenyl, 3-methoxy-2-hydroxypropyl, 3-ethoxy-2-hydroxypropyl, 3-propoxy-2-hydroxypropyl, 2-isopropoxy-2-hydroxypropyl, 3-n-butoxy-2-hydroxypropyl, 3-isobutoxy-2-hydroxypropyl, 3-sec-butoxy-2-hydroxypropyl, 3-tert-butoxy-2-hydroxypropyl, 3-n-amyloxy-2-hydroxypropyl, 3-sec-amyloxy-2-hydroxypropyl, 3-tert-amyloxy-2-hydroxypropyl, 3-isoamyloxy-2-hydroxypropyl, 3-n-hexyloxy-2-hydroxypropyl, 3-cyclohexyloxy-2-hydroxypropyl, 3-n-heptyloxy-2-hydroxypropyl, 3-n-octyloxy-2-hydroxypropyl, 3-(2-ethylhexyl)oxy-2-hydroxypropyl, 3-nonyloxy-2-hydroxypropyl, 3-isononyloxy-2-hydroxypropyl, 3-decyloxy-2-hydroxypropyl, 3-isodecyloxy-2-hydroxypropyl, 3-undecyloxy-2-hydroxypropyl, 3-lauryloxy-2-hydroxypropyl, 3-tridecyloxy-2-hydroxypropyl, 3-isotridecyloxy-2-hydroxypropyl, 3-myristyloxy-2-hydroxypropyl, 3-cetyloxy-2-hydroxypropyl, 3-isocetyloxy-2-hydroxypropyl, 3-stearyloxy-2-hydroxypropyl, 3-isostearyloxy-2-hydroxypropyl, 3-oleyloxy-2-hydroxypropyl, 3-behenyloxy-2-hydroxypropyl and the like groups.
As R2, R5, R7, R9, R11, R13, R15 and R18, there may be mentioned hydrogen atom and methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-amyl, sec-amyli tert-amyl, isoamyl, n-hexyl, cyclohexyl, n-heptyl, n-octyl, 2-ethylhexyl, nonyl, isononyl, decyl, isodecyl, undecyl, lauryl, tridecyl, isotridecyl, myristyl, cetyl, isocetyl, stearyl, isostearyl, oleyl, behenyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxyisopropyl, 2-hydroxy-n-butyl, 2-hydroxyisobutyl, 2-hydroxy-sec-butyl, 2-hydroxy-tert-butyl, 2-hydroxy-n-amyl, 2-hydroxy-sec-amyl, 2-hydroxy-tert-amyl, 2-hydroxyisoamyl, 2-hydroxy-n-hexyl, 2-hydroxycyclohexyl, 2-hydroxy-n-heptyl, 2-hydroxy-n-octyl, 2-hydroxy-2-ethylhexyl, 2-hydroxynonyl, 2-hydroxyisononyl, 2-hydroxydecyl, 2-hydroxyisodecyl, 2-hydroxyundecyl, 2-hydroxylauryl, 2-hydroxytridecyl, 2-hydroxyi-sotridecyl, 2-hydroxymyristyl, 2-hydroxycetyl, 2-hydroxyisocetyl, 2-hydroxystearyl, 2-hydroxyisostearyl, 2-hydroxyoleyl, 2-hydroxybehenyl, 2-methoxy-2-hydroxypropyl, 2-ethoxy-2-hydroxypropyl, 3-propoxy-2-hydroxypropyl, 2-isopropoxy-2-hydroxypropyl, 3-n-butoxy-2-hydroxypropyl, 3-isobutoxy-2-hydroxypropyl, 3-sec-butoxy-2-hydroxypropyl, 3-tert-butoxy-2-hydroxypropyl, 3-n-amyloxy-2-hydroxypropyl, 3-sec-amyloxy-2-hydroxypropyl, 3-tert-amyloxy-2-hydroxypropyl, 3-isoamyloxy-2-hydroxypropyl, 3-n-hexyloxy-2-hydroxypropyl, 3-cyclohexyloxy-2-hydroxypropyl, 3-n-heptyloxy-2-hydroxypropyl, 3-n-octyloxy-2-hydroxypropyl, 3-(2-ethylhexyl)oxy-2-hydroxypropyl, 3-nonyloxy-2-hydroxypropyl, 3-isononyloxy-2-hydroxypropyl, 3-decyloxy-2-hydroxypropyl, 3-isodecyloxy-2-hydroxypropyl, 3-undecyloxy-2-hydroxypropyl, 3-lauryloxy-2-hydroxypropyl, 3-tridecyloxy-2-hydroxypropyl, 3-isotridecyloxy-2-hydroxypropyl, 3-myristyloxy-2-hydroxypropyl, 3-cetyloxy-2-hydroxypropyl, 3-3-isocetyloxy-2-hydroxypropyl, 3-stearyloxy-2-hydroxypropyl, 3-isostearyloxy-2-hydroxypropyl, 3-oleyloxy-2-hydroxypropyl, 3-behenyloxy-2-hydroxypropyl and the like groups.
The cysteine or cystine derivatives represented by the above-described general formula (I), (II), (III) or (IV) may be either in the optically active form or racemic form. Among them, L and DL forms are preferred. As the salts of the compound represented by the above-described general formula (I), (II), (III) or (IV), there may be mentioned hydrohalogenides such as hydrochloride, hydrobromide, hydroiodide and the like; salts of an inorganic acid such as sulfate, carbonate, phosphate and the like; and salts of an organic acid such as acetate, tartrate, citrate, p-toluenesulfonate, glycolate, malate, lactate, fatty acid salt, acidic amino acid salts, pyrroglutamate and the like. These salts may be used either singly or in combination.
Next will be made a description of a process for producing the compounds of the present invention.
The cysteine or cystine derivative represented by the above-described general formula (I), (II), (III) or (IV) can be led to its amide or ester from by reacting, for example, L- or DL-cysteine or L- or DL-cystine with an acid anhydride, acid chloride, alkyl halide, epoxy alkane or alkyl glycidyl ether, whereby the amino group is acylated, alkylated, hydroxyalkylated or 3-alkoxy-2-hydroxypropylated, and then subjecting the resulting compound to dehydration-condensation with an alkyl amine or an alcohol.
The cysteine or cystine derivative represented by the above-described general formula (I) or (IV) can be produced, for example, by reacting L- or DL-cysteine amide or L- or DL-cystine diamide with an acid anhydride, acid chloride, alkyl halide, epoxy alkane or alkyl glycidyl ether, whereby the amino group is acylated, alkylated, hydroxyalkylated or 3-alkoxy-2-hydroxypropylated.
The cysteine or cystine derivative represented by the above-described general formula (II), (III) or (IV) can be produced, for example, by reacting L- or DL-cysteine ester or L- or DL-cystine diester with an acid anhydride, acid chloride, alkyl halide, epoxy alkane or alkyl glycidyl ether, whereby the amino group is acylated, alkylated, hydroxyalkylated or 3-alkoxy-2-hydroxypropylated.
In the next place, the above-described Component (B) to be used, in combination with the compound of the present invention, for preparing the cosmetic composition or dermatologic preparation for external use according to the present invention.
As the antioxidant as Component (B), there may be mentioned ascorbic acid, sodium ascorbate, ascorbyl stearate, ascorbyl palmitate, ascorbyl dipalmitate, magnesium ascorbate phosphate, xcex1-tocopherol, xcex2-tocopherol, xcex3-tocopherol, xcex4-tocopherol, xcex1-tocotrienol, xcex2-tocotrienol, xcex3-tocotrienol, xcex4-tocotrienol, tocopherol acetate, natural vitamin E, tocopherol nicotinate, Trolox, N-acetylcysteine, xcex1-lipoic acid, dehydrolipoic acid, glutathione, uric acid, dihydroxytoluene, butylhydroxyanisole, dibutylhydroxytoluene, erysorbic acid, sodium erysorbate, gallic acid, propyl gallate, tannic acid, catechin, caffeic acid, ferulic acid, protocatechuic acid, oryzanol, quercetin, epigallocatechin gallate, carnosol, sesamol, sesamine, sesamolin, zingerone, Shogaol, capsaicin, vanillyl amide, ellagic acid, bromophenol, flavoglacin, melanoidine, retinol, dehydroretinol, vitamin A oil, retinol acetate, retinol palmitate, retinal, retinoic acid, riboflavin, riboflavin butyrate ester, flavin mononucleotide, flavin adenine dinucleotide, superoxide dismutase, ubiquinol, ubiquinone, catalase, glutathione peroxidase, catalase ferroxidase, metallothionein, ceruloplasmin, transferrin, lactoferrin, albumin, bilirubin, citric acid, tartaric acid, malic acid, phytic acid, histidine, tryptophan, O-phosphono-pyridoxylidene rhodamine, N-(2-hydroxybenzyl)amino acid as described in U.S. Pat. No. 5,594,012, N-(4-pyridoxylmethylene)amino acid and the like.
As the anti-inflammatory drug as Component (B), there may be mentioned glycyrrhetinic acid, glyceryl glycyrrhetinate, stearyl glycyrrhetinate, glycyrrhetinyl stearate, glycyrrhizic acid, methyl glycyrrhizinate, dipotassium glycyrrhizinate, salicylic acid, sodium salicylate, resorcin, guaiazulene, allantoin, lithospermum root extract, shikonin, diphenhydramine hydrochloride, chlorpheniramine maleate, ichthammol, xcex3-oryzanol, thianthol, sodium copper chlorophyllin, ibuprofen, indomethacin, tranexamic acid, hydrocortisone and the like.
As the ultraviolet absorber as Component (B), there may be mentioned 2-hydroxy-4-methoxybenzophenone (oxybenzone), 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, sodium 2-hydroxy-4-methoxybenzophenone-5-sulfonate, dihydroxydimethoxybenzophenone, sodium dihydroxydimethoxybenzophenonesulfonate, 2,4-dihydroxybenzophenone, tetrahydroxybenzophenone, p-aminobenzoic acid, sodium p-aminobenzoate, ethyl p-aminobenzoate, glyceryl p-aminobenzoate, amyl p-dimethylaminobenzoate, 2-ethylhexyl p-dimethylaminobenzoate, ethyl p-methoxycinnamate, isopropyl p-methoxycinnamate, 2-ethylhexyl p-methoxycinnamate (cinnoxate), 2-ethoxyethyl p-methoxycinnamate, sodium p-methoxycinnamate, potassium p-methoxycinnamate, glyceryl di(p-methoxycinnamic acid)mono-2-ethylhexanoate, methyl diisopropylcinnamate, 2-ethylhexyl salicylate, phenyl salicylate, homomenthyl salicylate, dipropylene glycol salicylate, ethylene glycol salicylate, myristyl salicylate, methyl salicylate, 4-tert-butyl-4xe2x80x2-methoxydibenzoylmethane, 2-(2xe2x80x2-hydroxy-5xe2x80x2-methylphenyl)benzotriazole, methyl anthranilate, ethyl anthranilate, urocanic acid, ethyl urbcanate, 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]-1,3,5-triazine, titanium oxide, 3,3xe2x80x2-(1,4-phenylenedimethylidene)bis(7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptane-1-methanesulfonic acid) (Mexoryl SX), and the like.
Next will be made a description of the way of administering the oxidative stress inhibitor of the present invention.
The oxidative stress inhibitor of the present invention represented by the above-described general formula (I) or (II) can be administered orally or parenterally, but direct administration to an oxidative stress activating system is preferred. Usually, preferred is the use thereof in the form where it is incorporated in a cosmetic composition or dermatologic preparation for external use. In the method of the present invention for preventing, retarding, alleviating or treating a dermal change induced by an oxidative stress or wrinkles or flabbiness of the skin induced by light, preferred is direct administration of a cosmetic composition or dermatologic preparation for external use containing the compound of the above-described general formula (III) to the healthy skin or to any site wherein a dermal change or formation of wrinkles or flabbiness has advanced or is advancing.
When the compound represented by the above-described general formula (I), (II) or (III), or the above-described Components (A) and (B) are incorporated in a cosmetic composition as an effective ingredient for prevention or alleviation of skin injuries caused by an oxidative stress, it can be added in an amount of 0.01 to 10 wt. %, preferably 0.1 to 5 wt. %. When the compound represented by the above-described general formula (I), (II) or (III) or the above-described Components (A) and (B) are incorporated in a dermatologic preparation for external use as an effective ingredient for prevention or treatment of diseases induced from an oxidative stress, it can be added in an amount of 0.01 to 50 wt. %, preferably 0.1 to 20 wt. %. When the amount is less than 0.01 wt. %, the resulting preparation cannot fully exhibit oxidative stress inhibiting function, while when the amount exceeds 50 wt. %, on the other hand, it involves problems in feeling upon use such as creaky feeling onto the skin, and the like. Therefore, amounts outside the above range are not preferred.
It is preferred to continuously apply, to the skin, the cosmetic composition or dermatologic preparation for external use containing the compound represented by the above-described general formula (I), (II) or (III) or the above-described Components (A) and (B) for a long period of time, more specifically, for at least one month. It is more preferred that for the prevention of skin injuries or rag diseases caused by an oxidative stress, the preparation is continuously applied for a period not less than 3 months to the death of the patient, while for the alleviation or treatment of the skin injuries or diseases caused by an oxidative stress, it is applied for a period not less than 3 months to 10 years.
Application frequency preferably ranges from once/week to 5 times/day, with once/day to three times/day being more preferred. The amount of the compound represented by the above-described general formula (I), (II) or (III), or the above-described Components (A) and (B) to be applied preferably ranges from 0.003 xcexcg/cm2 to 200 mg/cm2, with 1 xcexcg/cm2 to 50 mg/cm2 being more preferred.
When the compound represented by the above-described general formula (I), (II) or (III), or the above-described Components (A) and (B) are incorporated in a cosmetic composition or a dermatologic preparation for external use, components ordinarily employed for a cosmetic composition or dermatologic preparation for external use can be, in addition to the oxidative stress inhibitor of the present invention, added within an extent not damaging the advantages of the present invention.
As such components ordinarily employed for a cosmetic composition or a dermatologic preparation for external use, there may be mentioned oily raw materials, surfactants, solvents, humectants, high-molecular weight substances, powdery substances, colorants, perfumes, percutaneous absorption promoters, components derived from animals or plants, and the like.
As the oily raw material, there may be mentioned oils and fats such as animal and vegetable oils, waxes such as lanolin, hydrocarbons such as paraffin, higher alcohols such as cetanol, higher fatty acids such as stearic acid, sterols, phospholipids such as lecithin, synthetic esters such as myristic acid, metal soaps, silicone oils and the like.
As the surfactant, there may be mentioned anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants, emulsifiers, solubilizing agents, and the like.
As the solvent, there may be mentioned lower alcohols such as ethanol, ethers, glycerins, liquid nonionic surfactants, liquid oily raw materials, other organic solvents, water, and the like.
As the humectant, there may be mentioned polyhydric alcohols such as glycerin, salts of an organic acid such as pyrrolidonecarboxylic acid, urea, mucopolysaccharides such as hyaluronic acid, salts of an amino acid such as proline, and the like.
As the high molecular weight substance, there may be mentioned natural high molecular weight compounds such as collagen, semi-synthetic high molecular weight compounds such as partially deacetylated chitin, synthetic high molecular weight compounds such as carboxymethyl cellulose, and the like.
As the powdery substance, there may be mentioned inorganic pigments such as talc, functional pigments such as synthetic mica, hybrid fine powder, pearl-lustrous pigments such as titanium-dioxide coated mica, photochromic pigments, high molecular powders such as nylon powder, organic powders such as Nxcex5-lauroyl lysine, and the like.
As the colorant, there may be mentioned legal 1st-class tar pigments, legal 2nd-class tar pigments, legal 3rd-class tar pigments, hair dyes, natural colorants, mineral colorants, and the like.
As the perfume, there may be mentioned animal perfumes such as musk, plant perfumes such as jasmine oil, synthetic perfumes such as xcex1-amylcinnamaldehyde, mixed perfumes, and the like.
As percutaneous absorption promoters, there may be mentioned urea, 2-pyrrolidone, 1-hexanol, 1-octanol, 1-decanol, 1-menthol, sodium lauryl sulfate, isopropyl myristate, n-hexyl acetate, oleic acid, and the like.
As the components derived from animals or plants, there may be mentioned licorice extract, placenta extract, aqueous hamamelis, and the like.
No particular limitations are imposed on the dosage form of the cosmetic composition or dermatologic preparation for external use containing the above-described general formula (I), (II) or (III) or the above-described Components (A) and (B), and any dosage form such as solution, paste, gel, solid or powder can be adopted. The cosmetic composition or dermatologic preparation for external use according to the present invention can be used as or for oil, lotion, cream, milky lotion, gel, shampoo, hair rinse, hair conditioner, enamel, foundation, lipstick, face powder, pack, ointment, tablet, injection, granule, capsule, perfume, powder, eau de Cologne, dental paste, soap, aerosol, cleansing foam and the like; and also as or for skin aging preventive or alleviative, skin inflammation preventive or alleviative, bath agent, hair tonic, skin vitalizing lotion, sunburn preventive, preventive or alleviative of photosensitivity such as xeroderma pigmentosum or solar urticaria, preventive or alleviative of photoallergy, preventive or alleviative of optical immunosuppression, preventive or alleviative of rough skin caused by injury, chaps, cleft or the like, and the like. It can be used as or for a preventive and/or curative for various diseases induced by the activation of an oxidative stress, e.g., rheumatic diseases such as rheumatoid arthritis and the like, arthritis, skin diseases such as atopic dermatitis, contact dermatitis, psoriasis vulgaris and the like, respiratory diseases such as bronchial asthma, bronchitis and the like, inflammatory bowel diseases, acute or chronic hepatitis, acute or chronic nephritis, Mediterranean fever, ischemic diseases such as myocardial infarction, and the like.
To the cosmetic composition or dermatologic preparation for external use containing the compound represented by the above-described general formula (I), (II) or (III) or the above-described Components (A) and (B), other ordinarily employed components in cosmetic compositions or dermatologic preparations for external use a can be added within an extent not impairing the advantages of the present invention. As such other ordinarily employed components in cosmetic compositions or dermatologic preparations for external use, there may be mentioned antiseptic bactericides, antioxidants, chelating agents, discoloration preventives, buffers, medicaments for acne vulgaris, antidandruffs or antipruritics, antiperspirants or antibromics, antipyrotics, acaricides or pediculicides, keratin softeners, medicaments for xeroderma, virucides, hormones, vitamins, amino acids, peptides, proteins, astringents, coolants, melanin synthesis inhibitors (whitening agents), antibiotics, antimycotics, hair growth promoters and the like.
The present invention will be hereinafter described in greater detail with reference to Examples (Synthesis Examples, Test Examples and Formulation Examples). It should however be borne in mind that the present invention is not limited to or by these Examples. In these Examples, the amount of each component is indicated by wt. %.